Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:12]=[N:13][N:14]([CH3:19])[C:15]=1[C:16]([OH:18])=[O:17]>>[C:8]([C:6]1[N:7]=[C:2]([C:11]2[CH:12]=[N:13][N:14]([CH3:19])[C:15]=2[C:16]([OH:18])=[O:17])[CH:3]=[CH:4][CH:5]=1)#[N:9]
Reactant: Cn1ncc(I)c1C(=O)O
Reactant: N#Cc1cccc(Br)n1
Product: Cn1ncc(-c2cccc(C#N)n2)c1C(=O)O
Yield: 0.5 %

Procedure:
Using 6-bromopicolinonitrile (0.73 g) and 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid (1 g), the title compound (4.7 mg) was obtained in the form of a colorless solid by the same method as that of (Example 3.22) <Step 1> or a method equivalent thereto.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](Cl)(=[O:45])=[O:44])=[O:36]>CN(C)C=O>[CH3:33][O:34][C:35](=[O:36])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](=[O:44])(=[O:45])[NH:24][C@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2C(=O)OC)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 2-(methoxycarbonyl)-benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 75 mg. MS (ES+): m/e=549 (M+H+).
Reaction SMILES: C1(C)C=CC(S(OC[C@@H:12]([CH3:19])[CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=O)=O)=CC=1.[C-:21]#[N:22].[Na+].[CH2:24](O)C>O>[C:15]([O:14][CH2:13][CH2:12][C@@H:19]([CH3:24])[C:21]#[N:22])([CH3:16])([CH3:17])[CH3:18]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)COC(C)(C)C)cc1
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: C[C@@H](C#N)CCOC(C)(C)C
Temperature: 0 °C

Procedure:
A mixture of 6.4 g. (0.021 mole) of (S)-(+)-3-tert. butoxy-2-methyl-1-propyl p-toluenesulfonate and 2.09 g. (0.043 mole) of sodium cyanide in 63 ml. of ethanol and 7 ml. of water was stirred and refluxed for 11 hours. After cooling, the reaction mixture was diluted with ice-water and worked up by extraction with CH2Cl2 in the manner of Example 1. The crude product (3.7 g.) was chromatographed on 125 g. of silica gel. Elution with 4:1 parts by volume hexane-ether gave 2.98 g. (91.7%) of R-(+)-4-tert.-butoxy-3-methylbutyronitrile as a colorless liquid.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C(#N)C>[CH2:3]([CH:2]([NH:1][C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:5][CH3:6])[CH3:4]
Reactant: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Reactant: CCC(N)CC
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1NC(CC)CC

Procedure:
3-Aminopentane (0.6 mL) was added to a solution of ethyl 2-(7-chloro-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (130 mg) in acetonitrile (5 mL), followed by heating under reflux overnight. After cooling the reaction solution, water was added thereto. The mixture was extracted twice with ethylacetate, and the organic layer was washed with an aqueus saturated solution of sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give the title compound (84 mg) as a green oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([Cl:18])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:20]([C:23]1([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][CH:30]=[CH:29]3)[CH2:25][CH2:24]1)[CH:21]=O>C(O)C>[Cl:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]3[N:7]([C:20]([C:23]4([C:26]5[CH:27]=[C:28]6[C:33](=[CH:34][CH:35]=5)[N:32]=[CH:31][CH:30]=[CH:29]6)[CH2:25][CH2:24]4)=[CH:21][N:1]=3)[CH:6]=2)[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: COC(=O)c1ccc(-c2cnc(N)nc2)cc1Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-(2-aminopyrimidin-5-yl)-2-chlorobenzoate (0.22 g, 0.83 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.20 g, 0.83 mmol) in ethanol (6 mL) was stirred at 100° C. overnight. The reaction mixture was concentrated to afford the crude product which was directly used for next step. LCMS: (M+H)=455.1/457.1.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1>>[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-2″(1′H)-one, 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3-indole]-6-carbonitrile was obtained (89%) as a colorless solid: mp 151-153° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=3.9 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.34-6.84 (m, 9H), 5.19 (d, J=15.8 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.97 (d, J=15.8 Hz, 1H), 4.79 (d, J=9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.3, 160.7, 155.1, 149.7, 142.3, 137.1, 134.8, 131.2, 129.5, 125.8, 124.6, 123.8, 122.9, 121.8, 118.5, 113.8, 113.3, 109.9, 80.21, 77.5, 57.9, 46.1; MS (ES+) m/z 353.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>C(Cl)Cl>[C:7]([O:6][C:4]([C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[NH:1][C:24](=[O:25])[CH2:23][Br:22])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1NC(=O)CBr
Yield: 102.5 %

Procedure:
To a mixture of tert-butyl 2-aminobenzoate (5.79 g.), triethylamine (3.99 g.) in methylene chloride (100 ml.) was added dropwise bromoacetyl bromide (8.01 g.) over a period of 15 minutes with stirring under ice-cooling at 5° to 10° C. followed by stirring for 1.75 hours at the same temperature. The reaction mixture was washed successively with 1M aqueous solution of citric acid (50 ml.×2), water a satirated aqueous solution of sodium bicarbonate (25 ml.×2), water and an aqueous solution of sodium chloride, dried over magnesium, treated with activated charcoal and then evaporated to give an oil of the title compound (9.65 g.).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[N:15]([O-:17])=[O:16].[Na+].C(OC(C)C)(=O)C.II>O>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Reactant: O=N[O-]
Agent: II
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 50 °C
Yield: 77.1 %

Procedure:
Into a reactor, equipped with a reflux condenser and under inert gas, 8-fluoro-2H-chromene-5-carboxylic acid amide (4.94 g; 25.6 mmoles), sodium nitrite (4.4 g; 64 mmoles) and isopropyl acetate (40 ml) were charged. The mixture was kept under mechanic stirring and heated at 50° C. In one portion iodine (1.9 g; 7.5 mmoles) and then, in 3 hours, Oxistrong 15® (6 ml) were added. At the end of the addition the reaction mixture was kept under stirring for 1 hour and cooled to 20° C. After addition of water (30 ml), the mixture was further cooled at 5° C. for 1 hour. The solid was filtered and washed with isopropyl acetate (3×10 ml), pre-cooled at 0° C., and with water (2×10 ml). After drying in oven under vacuum at 50° C. overnight, 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (4.7 g; HPLC titre 90%; 70% yield) was obtained. The mother liquors of the reaction were treated with a 15% solution of sodium metabisulphite (20 ml) up to decoloration. The phases were separated, the organic phase was dried and the organic solvent was removed under reduced pressure obtaining a solid (0.8 g) containing 49% of 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide. Overall yield: 76.4%.
Reaction SMILES: [C:1]12([NH:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=4)[N:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O>[C:1]12([NH:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=4)[N:15]=[C:14]([NH:29][CH2:26][CH:27]=[CH2:28])[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=CCN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(NC34CC5CC(CC(C5)C3)C4)c2c1
Solvent: O
Product: C=CCNc1nc(NC23CC4CC(CC(C4)C2)C3)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To 82 mg (0.25 mmol) of 4-(1-adamantylamino)-2-chloro-6-nitroquinazoline was added 1.00 ml (13.33 mmol) of allylamine, and the resulting mixture was stirred at room temperature overnight. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 77 mg (88.7%) of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:25]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][C:18]([F:17])([F:28])[F:29])=[CH:21][CH:22]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C1N(Cc2ccc(OC(F)(F)F)cc2)CCC12CCC(O)CC2

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with 4-trifluoromethoxybenzylamine as a mixture of cis and trans diastereomers. Light yellow viscous oil. MS (m/e): 344.147 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([S:18][C@@H:16]([CH3:17])[C@@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: C[C@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)S[C@@H](C)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To dichloromethane (1 ml) was added (2S,3S)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (3 mg), followed by addition of a dichloromethane solution of triethylamine (10%, 16 μl) with ice-cooling. Then, a dichloromethane solution of acetyl chloride (10%, 8.2 μl) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel chromatography (1×1 cm) using ethyl acetate-hexane (2:1) as the eluent. The desired fraction was concentrated to give (2S,3S)-3-acetylthio-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 44:1.2 mg) as a colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([CH2:16][O:17][C:18]2[C:23]3[C:24]([O:27][CH2:28][CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[N:25][O:26][C:22]=3[CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1)=O.C(OCC)(=O)C>C(OCC)C>[OH:8][CH2:9][C:11]1([CH2:16][O:17][C:18]2[C:23]3[C:24]([O:27][CH2:28][CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[N:25][O:26][C:22]=3[CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C1(COc2cccc3onc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4(CO)CCCC4)c23)CC1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a suspension of lithium aluminum hydride (50.7 mg, 1.34 mmol) in diethyl ether (5 mL) was added an ethereal solution (3 mL) of tert-butyl 4-{[(4-{[1-(methoxycarbonyl)cyclopentyl]methoxy}-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 51, step 2, 600 mg, 1.23 mmol) at 0° C. After being stirred for 30 min, ethyl acetate was added to the mixture. Then the mixture was washed with 2N hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 456 mg (81%) of the title compound as a white solid. The crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: Fc1ccccc1Cc1n[nH]c2nccnc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3nccnc32)n1

Procedure:
A solution of 144 mg (0.63 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine from example 14A, 92 mg (0.63 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 12 mg (0.013 mmol) of tris(di-benzylideneacetone)dipalladium, 18 mg (0.038 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 287 mg (0.88 mmol) of cesium carbonate in 4 ml of degassed toluene is heated at 90° C. for 20 h. It is then diluted with ethyl acetate and a little methanol and filtered with suction. The solid is again stirred with methanol and filtered off with suction once again. The filtrates are then combined and concentrated, and the residue is purified by preparative HPLC. The product fraction obtained is concentrated, again stirred with methanol and filtered off with suction. 13 mg (6% of theory) of the desired product are obtained in this way.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][C:23]([OH:25])=[O:24])=[O:34])(=[O:11])=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(O)CS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)acetic acid (44 mg, 0.11 mmol) in CH2Cl2 (2 ml) and acetonitrile (2 ml) was added mCPBA (27 mg, ˜0.11 mmol). The reaction was stirred at room temperature for 4 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 20-30% MeOH in EtOAc) followed by PTLC (25% MeOH in EtOAc) to yield the title compound (34 mg, 74%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9](/[CH:12]=[CH:13]/[CH:14]=[CH:24]/[CH:25]=[O:26])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=C/C=C/c1ccc(-n2cccn2)cc1
Product: O=C/C=C/C=C/c1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-[4-(1H-pyrazol-1-yl)phenyl]-2-propenal (prepared as described in Reference Example 30) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[CH3:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[N:36]=[CH:37][N:38]=[C:39]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:40]=2)[CH:20]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C3CCOCC3)[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2nc(C3CCOCC3)[nH]c12

Procedure:
33 mg (0.13 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 40 mg (0.12 mmol) 7-methyl-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 μL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 60° C. The reaction mixture was poured onto ice water and the precipitate formed was suction filtered. The precipitate was dissolved and then purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:23]([O:22][C:20](=[O:21])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH2:1][Br:30])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
4-Methyl-3-(trifluoromethyl)aniline (1.75 g, 10.0 mmol) was dissolved in DCM (10 mL), and pyridine (970 μL, 12.0 mmol) and then benzyl chloroformate (2 mL, 14.0 mmol) were dropwise added thereto. The resulting mixture was stirred at 0° C. for 0.5 hours. The organic layer was washed with a saturated sodium bicarbonate solution and saturated brine, sequentially, and then concentrated under reduced pressure. The residue was dissolved in 15 mL of carbon tetrachloride, and N-bromosuccinimide (2.67 g, 15.0 mmol) and 2,2-azobisisobutyronitrile (250 mg, 1.52 mmol) were added thereto. The resulting mixture was refluxed under heating for 1 hour. Insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate 20:1) to give [4-bromomethyl-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (1.04 g, 27%) as a light-yellow oil.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].Cl.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:13][N:14]=[N:15]2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([NH:5][CH2:4][CH2:3][Cl:2])(=[O:26])=[O:27])=[CH:23][CH:24]=3)=[CH:13][N:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Reactant: NCCCl
Agent: Cl
Product: O=S(=O)(NCCCl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1

Procedure:
This compound is prepared in a similar manner to the procedure of Example 10 using equimolar quantities of 2-chloroethylamine hydrochloride instead of 3-chloropropylamine hydrochloride and 4-(7-chloro-4-cinnolinylamino)benzenesulphonyl chloride hydrochloride instead of 4-(7-chloro-4-quinolinylamino)benzenesulphonyl chloride.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.Cl>>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([N:33]3[CH2:34][C:31]([F:35])([F:30])[CH2:32]3)=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Reactant: FC1(F)CNC1
Agent: Cl
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)N2CC(F)(F)C2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (Example 147c) and 3,3-Difluoro-azetidine; hydrochloride (CAN 288315-03-7) as starting materials and isolated (18 mg, 24%); MS (ESI, m/z): 490.5 (M+H+).
Reaction SMILES: CC1C=CC(S([N:11]2[CH:15]=[C:14]([CH:16]=O)[CH:13]=[N:12]2)(=O)=[O:9])=CC=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O.O>[OH2:9].[NH:11]1[CH:15]=[C:14]([CH2:16][N:18]2[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:25][C:26]2=[O:28])[CH:13]=[N:12]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cn2)cc1
Reactant: Nc1ccccc1CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2ccccc2N1Cc1cn[nH]c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer, 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x58 (1.65 g, 6.6 mmol) is dissolved in a 1/1 mixture of THF/H2O (50 ml) and the solution containing (2-aminophenyl)acetic acid x96 (1 g, 66 mmol) is added. The pH is adjusted to 5 with acetic acid and the mixture is cooled to 0° C. Sodium triacetoxyborohydride (2.10 g, 10 mmol) is added and the mixture is stirred overnight at room temperature. Water is added and the aqueous phase is extracted three times with CH2Cl2. The combined organic phases are washed with brine, dried over MgSO4 and evaporated. Purification of the residue by preparative chromatography on silicagel and recrystallization from AcOEt affords 106 mg of pure 1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one hydrate 173.